SlLica Activates NfkB

The first notion that silica causes NF-kB activation was identified in an experimental system using a mouse peritoneal macrophage cell line as a prototype model.89 Since then, NF-kB activation by silica has been documented in a variety of cellular systems.90-95 Chen et al.96 postulated that silica activated NF-kB through proteolytic degradation of IkBol However, degradation of IKBa in the cells treated with silica was not inhibited by a classic proteasome inhibitor, MG132. In contrast, an inhibitor for calpains attenuated the degradation of IKBa and NF-kB activation induced by silica. Recent studies by Kang et al.90 reported that tyrosine phosphorylation of IKa may contribute to silica-induced IKBa degradation.

The majority of studies on silica-induced NF-kB activation were conducted through in vitro silica exposure of selected cell types. Only a few studies have examined the effect of silica on NF-kB in vivo. Using bronchoalveolar lavage cells from rats exposed to silica, Porter et al.97 demonstrated that NF-kB activation in the silica-exposed rats increased progressively throughout the 116-day silica inhalation period. The expression of two NF-KB-regulated cytokines, TNFa and IL-1, was correlated with the induction of NF-kB by silica. In transgenic mice carrying a NF-KB-dependent luciferase reporter gene, instillation of silica caused NF-kB activation in both alveolar macrophages and epithelial cells at 24 to 72 h postinstillation.95

The signal transduction pathways for NF-kB activation are well characterized for cellular responses to inflammatory cytokines, LPS, HTLV Tax protein, and CD28 signals.98 It is unknown, however, whether silica activates NF-kB through similar signaling cascades. A number of reports indicated that silica was capable of inducing generation of ROS in the cells (see Section 4.3.4). Although it is still a debatable issue, ROS have long been assumed to be critical mediators for the NF-kB signaling.99

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